The present invention is directed to advantageous processes for the preparation of 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and analogs, and to a crystalline, hydrated dihydrochloride salt thereof having advantageous properties.
Reiter, U.S. Pat. No. 4,560,690 has described 2-(1-pentyl-3-guanidino)-4-(2-methyl-4-imidazolyl)thiazole and various analogs, compounds having valuable antiulcer activity. That patent, which further details pharmaceutical compositions and a method of inhibiting ulcers with these compounds, is included herein by reference.
Reiter prepared the subject compounds via the following reaction scheme: ##STR1## wherein R is benzyl or (C.sub.1 -C.sub.5)alkyl and R.sup.1 is (C.sub.1 -C.sub.5)alkyl. The products were generally isolated as their dihydrobromide salts and converted to preferred dihydrochloride salts via their free base forms. This route employs toxic reagents, sodium dicyanamide and hydrogen sulfide, presenting environmental problems. In particular, the use of large excesses of hydrogen sulfide (or alternatively hydrogen sulfide under pressure) presents particular problems which limit batch sizes. This old scheme further lacks flexibility, it being necessary to carry out the entire sequence for each compound of the formula (I) that is desired.